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Background: A number of accelerator-based isotope production facilities utilize 100- to 200-MeV proton beams due to the high production rates enabled by high-intensity beam capabilities and the greater diversity of isotope production brought on by the long range of high-energy protons. However, nuclear reaction modeling at these energies can be challenging because of the interplay between different reaction modes and a lack of existing guiding cross-section data. Purpose: A Tri-lab collaboration has been formed among the Lawrence Berkeley, Los Alamos, and Brookhaven National Laboratories to address these complexities by characterizing charged-particle nuclear reactions relevant to the production of established and novel radioisotopes. Method: In the inaugural collaboration experiments, stacked-targets of niobium foils were irradiated at the Brookhaven Linac Isotope Producer (Ep=200MeV) and the Los Alamos Isotope Production Facility (Ep=100MeV) to measure Nb93(p,x) cross sections between 50 and 200 MeV. First measurements of the Nb93(p,4n)Mo90 beam monitor reaction beyond 100 MeV are reported in this work, as part of the broadest energy-spanning dataset for the reaction to date. Nb93(p,x) production cross sections are additionally reported for 22 other measured residual products. The measured cross-section results were compared with literature data as well as the default calculations of the nuclear model codes TALYS, CoH, EMPIRE, and ALICE. Results: The default code predictions largely failed to reproduce the measurements, with consistent underestimation of the preequilibrium emission. Therefore, we developed a standardized procedure that determines the reaction model parameters that best reproduce the most prominent reaction channels in a physically justifiable manner. The primary focus of the procedure was to determine the best parametrization for the preequilibrium two-component exciton model via a comparison to the energy-dependent Nb93(p,x) data, as well as previously published La139(p,x) cross sections. Conclusions: This modeling study revealed a trend toward a relative decrease for internal transition rates at intermediate proton energies (Ep=20-60 MeV) in the current exciton model as compared to the default values. The results of this work are instrumental for the planning, execution, and analysis essential to isotope production.

OBJECTIVE: The purpose of this study was to examine whether baseline sleep duration predicts weight loss outcomes in a randomized controlled trial examining a behavioral weight loss (BWL) intervention among overweight and obese (OW/OB) women with urinary i

Combinatorial control by multiple transcription factors (TFs) is a hallmark of eukaryotic gene regulation. Despite its prevalence and crucial roles in enhancing specificity and integrating information, the mechanisms behind why eukaryotic TFs depend on one another, and whether such interdependence evolves, are not well understood. We exploit natural variation in co-TF dependence in the yeast phosphate starvation (PHO) response to address this question. In the model yeast Saccharomyces cerevisiae , the main TF, Pho4, relies on the co-TF Pho2 to regulate ~28 genes. In a related yeast pathogen, Candida glabrata , its Pho4 exhibits significantly reduced Pho2 dependence and has an expanded target set of ~70 genes. Biochemical analyses showed C. glabrata Pho4 (CgPho4) binds to the same consensus motif with 3-4-fold higher affinity than ScPho4 does. A machine-learning-based prediction and yeast one-hybrid assay identified two Intrinsically Disordered Regions (IDRs) in CgPho4 that boost the activity of the main activation domain but showed little to no activity on their own. We also found evidence for autoinhibition behind the co-TF dependence in ScPho4. An IDR in ScPho4 next to its DNA binding domain was found to act as a double-edged sword: it both allows for enhanced activity with Pho2, and inhibits Pho4's activity without Pho2. This study provides a detailed molecular picture of how co-TF dependence is mediated and how its evolution, mainly driven by IDR divergence, can lead to significant rewiring of the regulatory network.

Background: Friedreich ataxia is a rare genetic disorder associated with progressive mitochondrial dysfunction leading to widespread sequelae including ataxia, muscle weakness, hypertrophic cardiomyopathy, diabetes mellitus, and neuromuscular scoliosis. Children with Friedreich ataxia are at high risk for periprocedural complications during posterior spinal fusion due to their comorbidities., Aim: To describe our single-center perioperative management of patients with Friedreich ataxia undergoing posterior spinal fusion., Methods: Adolescent patients with Friedreich ataxia presenting for spinal deformity surgery between 2007 and 2023 were included in this retrospective case series performed at the Children's Hospital of Philadelphia. Perioperative outcomes were reviewed along with preoperative characteristics, intraoperative anesthetic management, and postoperative medical management., Results: Seventeen patients were included in the final analysis. The mean age was 15 ± 2 years old and 47% were female. Preoperatively, 35% were wheelchair dependent, 100% had mild-to-moderate hypertrophic cardiomyopathy with preserved systolic function and no left ventricular outflow tract obstruction, 29% were on cardiac medications, and 29% were on pain medications. Intraoperatively, 53% had transesophageal echocardiography monitoring; 12% had changes in volume status on echo but no changes in function. Numerous combinations of total intravenous anesthetic agents were used, most commonly propofol, remifentanil, and ketamine. Baseline neuromonitoring signals were poor in four patients and one patient lost signals, resulting in 4 (24%) wake-up tests. The majority (75%) were extubated in the operating room. Postoperative complications were high (88%) and ranged from minor complications like nausea/vomiting (18%) to major complications like hypotension/tachycardia (29%) and need for extracorporeal membrane oxygenation support in one patient (6%)., Conclusions: Patients with Friedreich ataxia are at high risk for perioperative complications when undergoing posterior spinal fusion and coordinated multidisciplinary care is required at each stage. Future research should focus on the utility of intraoperative echocardiography, optimal anesthetic agent selection, and targeted fluid management to reduce postoperative cardiac complications., (© 2024 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Background: Point-of-care ultrasound is an invaluable bedside tool for anesthesiologists and has been integrated into anesthesiology residency training and board certification in the United States. Little is known about point-of-care ultrasound training practices in pediatric anesthesia fellowship programs., Aims: To describe the current state of point-of-care ultrasound education in pediatric anesthesia fellowship programs in the United States., Methods: We conducted a cross-sectional survey study distributed to 60 American Accreditation Council for Graduate Medical Education-accredited pediatric anesthesia fellowship programs. Two programs were in their initial accreditation period and were excluded due to lack of historical data. Program directors or associate program directors were invited to complete this 23-item survey., Results: Thirty-three of fifty-eight programs (57%) completed the survey. Of those, 15 programs (45%) reported having a point-of-care ultrasound curriculum. Programs with ≤3 fellows per year were less likely to have an ultrasound curriculum compared to programs with ≥4 fellows per year (30% programs 0-3 fellows/year vs. 69% programs ≥4 fellows/year, odds ratio 0.19 [95% confidence intervals 0.04-0.87]; p = .03). Program directors and associate program directors rated point-of-care ultrasound training as highly valuable to fellows' education. Barriers to use most commonly included lack of experience (64%), lack of oversight/interpretive guidance (58%), and lack of time (45%). Programs without point-of-care ultrasound training had significantly higher odds of listing lack of ultrasound access as a primary barrier (50% programs without vs. 13% programs with, odds ratio 6.5, [95% confidence intervals 1.3-50]; p = .04)., Conclusions: This observational survey-based study suggests that fewer than half of pediatric anesthesia training programs in the United States offer point-of-care ultrasound education. Additional research is needed to optimize this education and training in pediatric anesthesia fellowship programs., (© 2024 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Background: Autism spectrum disorder (ASD) is a neurocognitive disorder characterized by impairments in communication and socialization. There are little data comparing the differences in perioperative outcomes in children with and without ASD. We hypothesized that children with ASD would have higher postoperative pain scores than those without ASD., Methods: Pediatric patients undergoing ambulatory tonsillectomy/adenoidectomy, ophthalmological surgery, general surgery, and urologic procedures between 2016 and 2021 were included in this retrospective cohort study. ASD patients, defined by International Classification of Diseases-9/10 codes, were compared to controls utilizing inverse probability of treatment weighting based on surgical category/duration, age, sex, race and ethnicity, anesthetizing location, American Society of Anesthesiology physical status, intraoperative opioid dose, and intraoperative dexmedetomidine dose. The primary outcome was the maximum postanesthesia care unit (PACU) pain score, and secondary outcomes included premedication administration, behavior at induction, PACU opioid administration, postoperative vomiting, emergence delirium, and PACU length of stay., Results: Three hundred thirty-five children with ASD and 11,551 non-ASD controls were included. Maximum PACU pain scores in the ASD group were not significantly higher than controls (median, 5; interquartile range [IQR], 0-8; ASD versus median, 5; IQR, 0-8 controls; median difference [95% confidence interval {CI}] of 0 [-1.1 to 1.1]; P = .66). There was no significant difference in the use of premedication (96% ASD versus 95% controls; odds ratio [OR], 1.5; [95% CI, 0.9-2.7]; P = .12), but the ASD cohort had significantly higher odds of receiving an intranasal premedication (4.2% ASD versus 1.2% controls; OR, 3.5 [95% CI, 1.8-6.8]; P < .001) and received ketamine significantly more frequently (0.3% ASD versus <0.1% controls; P < .001). Children with ASD were more likely to have parental (4.9% ASD versus 1.0% controls; OR, 5 [95% CI, 2.1-12]; P < .001) and child life specialist (1.3% ASD versus 0.1% controls; OR, 9.9 [95% CI, 2.3-43]; P < .001) presence at induction, but were more likely to have a difficult induction (11% ASD versus 3.4% controls; OR, 3.42 [95% CI, 1.7-6.7]; P < .001). There were no significant differences in postoperative opioid administration, emergence delirium, vomiting, or PACU length of stay between cohorts., Conclusions: We found no difference in maximum PACU pain scores in children with ASD compared to a similarly weighted cohort without ASD. Children with ASD had higher odds of a difficult induction despite similar rates of premedication administration, and significantly higher parental and child life specialist presence at induction. These findings highlight the need for future research to develop evidence-based interventions to optimize the perioperative care of this population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

A process for the production of tens to hundreds of GBq amounts of zirconium-88 ( 88 Zr) using proton beams on yttrium was developed. For this purpose, yttrium metal targets (≈20 g) were irradiated in a ~16 to 34 MeV proton beam at a beam current of 100-200 µA at the Los Alamos Isotope Production Facility (IPF). The 88 Zr radionuclide was produced and separated from the yttrium targets using hydroxamate resin with an elution yield of 94(5)% (1σ). Liquid DCl solution in D 2 O was selected as a suitable 88 Zr sample matrix due to the high neutron transmission of deuterium compared to hydrogen and an even distribution of 88 Zr in the sample matrix. The separated 88 Zr was dissolved in DCl and 8 µL of the obtained solution was transferred to a tungsten sample can with a 1.2 mm diameter hole using a syringe and automated filling station inside a hot cell. Neutron transmission of the obtained 88 Zr sample was measured at the Device for Indirect Capture Experiments on Radionuclides (DICER)., (© 2023. The Author(s).)

Injectable hydrogels may be pre-formed through dynamic crosslinks, allowing for injection and subsequent retention in the tissue by shear-thinning and self-healing processes, respectively. These properties enable the site-specific delivery of encapsulated therapeutics; yet, the sustained release of small-molecule drugs and their cell-targeted delivery remains challenging due to their rapid diffusive release and non-specific cellular biodistribution. Herein, we develop an injectable hydrogel system composed of a macrophage-targeted nanoparticle (cyclodextrin nanoparticles, CDNPs) crosslinked by adamantane-modified hyaluronic acid (Ad-HA). The polymer-nanoparticle hydrogel uniquely leverages cyclodextrin's interaction with small molecule drugs to create a spatially discrete drug reservoir and with adamantane to yield dynamic, injectable hydrogels. Through an innovative two-step drug screening approach and examination of 45 immunomodulatory drugs with subsequent in-depth transcriptional profiling of both murine and human macrophages, we identify celastrol as a potent inhibitor of pro-inflammatory (M1-like) behavior that furthermore promotes a reparatory (M2-like) phenotype. Celastrol encapsulation within the polymer-nanoparticle hydrogels permitted shear-thinning injection and sustained release of drug-laden nanoparticles that targeted macrophages to modulate cell behavior for greater than two weeks in vitro . The modular hydrogel system is a promising approach to locally modulate cell-specific phenotype in a range of applications for immunoregenerative medicine.

Tissue repair is largely regulated by diverse Mϕ populations whose functions are timing- and context-dependent. The early phase of healing is dominated by pro-inflammatory Mϕs, also known as M1, followed by the emergence of a distinct and diverse population that is collectively referred to as M2. The extent of the diversity of the M2 population is unknown. M2 Mϕs may originate directly from circulating monocytes or from phenotypic switching of pre-existing M1 Mϕs within the site of injury. The differences between these groups are poorly understood, but have major implications for understanding and treating pathologies characterized by deficient M2 activation, such as chronic wounds, which also exhibit diminished M1 Mϕ behavior. This study investigated the influence of prior M1 activation on human Mϕ polarization to an M2 phenotype in response to IL-4 treatment in vitro. Compared to unactivated (M0) Mϕs, M1 Mϕs up-regulated several receptors that promote the M2 phenotype, including the primary receptor for IL-4. M1 Mϕs also up-regulated M2 markers in response to lower doses of IL-4, including doses as low as 10 pg/mL, and accelerated STAT6 phosphorylation. However, M1 activation appeared to also change the Mϕ response to treatment with IL-4, generating an M2-like phenotype with a distinct gene and protein expression signature compared to M2 Mϕs prepared directly from M0 Mϕs. Functionally, compared to M0-derived M2 Mϕs, M1-derived M2 Mϕs demonstrated increased migratory response to SDF-1α, and conditioned media from these Mϕs promoted increased migration of endothelial cells in transwell assays, although other common Mϕ-associated functions such as phagocytosis were not affected by prior polarization state. In summary, M1 polarization appears to prime Mϕs to transition into a distinct M2 phenotype in response to IL4, which leads to increased expression of some genes and proteins and decreased expression of others, as well as functional differences. Together, these findings indicate the importance of prior M1 activation in regulating subsequent M2 behavior, and suggest that correcting M1 behavior may be a therapeutic target in dysfunctional M2 activation., (©2021 Society for Leukocyte Biology.)

Evidence that long non-coding RNAs (lncRNAs) participate in DNA repair is accumulating, however, whether they can control DNA repair pathway choice is unknown. Here we show that the small Cajal body-specific RNA 2 (scaRNA2) can promote HR by inhibiting DNA-dependent protein kinase (DNA-PK) and, thereby, NHEJ. By binding to the catalytic subunit of DNA-PK (DNA-PKcs), scaRNA2 weakens its interaction with the Ku70/80 subunits, as well as with the LINP1 lncRNA, thereby preventing catalytic activation of the enzyme. Inhibition of DNA-PK by scaRNA2 stimulates DNA end resection by the MRN/CtIP complex, activation of ATM at DNA lesions and subsequent repair by HR. ScaRNA2 is regulated in turn by WRAP53β, which binds this RNA, sequestering it away from DNA-PKcs and allowing NHEJ to proceed. These findings reveal that RNA-dependent control of DNA-PK catalytic activity is involved in regulating whether the cell utilizes NHEJ or HR., (© 2022. The Author(s).)

225 Ac is a valuable medical radionuclide for targeted α therapy, but 227 Ac is an undesirable byproduct of an accelerator-based synthesis method under investigation. Sufficient detector sensitivity is critical for quantifying the trace impurity of 227 Ac, with the 227 Ac/ 225 Ac activity ratio predicted to be approximately 0.15% by end-of-bombardment (EOB). Superconducting transition edge sensor (TES) microcalorimeters offer high resolution energy spectroscopy using the normal-to-superconducting phase transition to measure small changes in temperature. By embedding 225 Ac production samples in a gold foil thermally coupled to a TES microcalorimeter we can measure the decay energies of the radionuclides embedded with high resolution and 100% detection efficiency. This technique, known as decay energy spectroscopy (DES), collapses several peaks from α decays into single Q-value peaks. In practice there are more complex factors in the interpretation of data using DES, which we will discuss herein. Using this technique we measured the EOB 227 Ac impurity to be (0.142 ± 0.005)% for a single production sample. This demonstration has shown that DES is a useful tool for quantitative measurements of complicated spectra., (Published by Elsevier Ltd.)

Developing targeted α-therapies has the potential to transform how diseases are treated. In these interventions, targeting vectors are labelled with α-emitting radioisotopes that deliver destructive radiation discretely to diseased cells while simultaneously sparing the surrounding healthy tissue. Widespread implementation requires advances in non-invasive imaging technologies that rapidly assay therapeutics. Towards this end, positron emission tomography (PET) imaging has emerged as one of the most informative diagnostic techniques. Unfortunately, many promising α-emitting isotopes such as 225 Ac and 227 Th are incompatible with PET imaging. Here we overcame this obstacle by developing large-scale (Ci-scale) production and purification methods for 134 Ce. Subsequent radiolabelling and in vivo PET imaging experiments in a small animal model demonstrated that 134 Ce (and its 134 La daughter) could be used as a PET imaging candidate for 225 Ac III (with reduced 134 Ce III ) or 227 Th IV (with oxidized 134 Ce IV ). Evaluating these data alongside X-ray absorption spectroscopy results demonstrated how success relied on rigorously controlling the Ce III /Ce IV redox couple.

With the mounting reports of culturally insensitive care and the reported challenges nurses experience when caring for culturally diverse patients, developing the intercultural readiness of nursing students is a necessity. However, little is known as to the success of cultural competence educational interventions in undergraduate nursing curricula and there remains a lack of consensus within the literature as to how it should be structured, organised and facilitated. Incorporating an integrative review method, this study synthesised international research on educational interventions used in preparing student nurses to care for culturally diverse patients. A systematic literature search of all published studies between 2013 and 2017, in CINAHL, Scopus, Medline, PubMed, Embase, Cochrane, Education Source and PsycINFO databases were performed. The PRISMA checklist was used to guide the review process. Six hundred and twenty-four studies were screened for eligibility and the analysis of the fourteen included studies are presented within two overarching themes; increasing knowledge and understanding and developing commitment and confidence. Engaging student nurses in learning activities that augment their understanding of, and commitment to, providing culturally competent care must include a variety of integrated culturally responsive pedagogical approaches made explicit and continuously developed across all learning opportunities., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We report the draft genome sequences of Bacillus glennii V44-8, Bacillus saganii V47-23a, and Bacillus sp. strain V59.32b, isolated from the Viking spacecraft assembly cleanroom, and Bacillus sp. strain MER&#95;TA&#95;151 and Paenibacillus sp. strain MER&#95;111, isolated from the Mars Exploration Rover (MER) assembly cleanroom., (Copyright © 2020 Becket et al.)

The clinically aggressive alveolar rhabdomyosarcoma (RMS) subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here, we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacologic combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion-positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent manner. This was pharmacologically mimicked by the BH3 mimetic navitoclax, identified as top compound in a screen from 208 targeted compounds. In a parallel approach, and to identify drugs that alter the stability of PAX3-FOXO1 protein, the same drug library was screened and fusion protein levels were directly measured as a read-out. This revealed that inhibition of Aurora kinase A most efficiently negatively affected PAX3-FOXO1 protein levels. Interestingly, this occurred through a novel specific phosphorylation event in and binding to the fusion protein. Aurora kinase A inhibition also destabilized MYCN, which is both a functionally important oncogene and transcriptional target of PAX3-FOXO1. Combined treatment with an Aurora kinase A inhibitor and navitoclax in FP-RMS cell lines and patient-derived xenografts synergistically induced cell death and significantly slowed tumor growth. These studies identify a novel functional interaction of Aurora kinase A with both PAX3-FOXO1 and its effector MYCN, and reveal new opportunities for targeted combination treatment of FP-RMS. SIGNIFICANCE: These findings show that Aurora kinase A and Bcl-2 family proteins are potential targets for FP-RMS., (©2019 American Association for Cancer Research.)

Macrophages are major upstream regulators of the inflammatory response to implanted biomaterials. Sequential functions of distinct macrophage phenotypes are essential to the normal tissue repair process, which ideally results in vascularization and integration of implants. Improper timing of M1 or M2 macrophage activation results in dysfunctional healing in the form of chronic inflammation or fibrous encapsulation of the implant. Thus, biphasic drug delivery systems that modulate macrophage behavior are an appealing approach to promoting implant integration. In this review, we describe the timing and roles of macrophage phenotypes in healing, then highlight current drug delivery systems designed to sequentially modulate macrophage behavior., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous Braf V600E Pten -/- melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti-CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non-small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15Rα complexes enhanced tumor control compared with either monotherapy., (©2019 American Association for Cancer Research.)

Proper repair of DNA double-strand breaks is critical for maintaining genome integrity and avoiding disease. Modification of damaged chromatin has profound consequences for the initial signaling and regulation of repair. One such modification involves ubiquitination by E3 ligases RNF8 and RNF168 within minutes after DNA double-strand break formation, altering chromatin structure and recruiting factors such as 53BP1 and BRCA1 for repair via non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively. The WD40 protein WRAP53β plays an essential role in localizing RNF8 to DNA breaks by scaffolding its interaction with the upstream factor MDC1. Loss of WRAP53β impairs ubiquitination at DNA lesions and reduces downstream repair by both NHEJ and HR. Intriguingly, WRAP53β depletion attenuates repair of DNA double-strand breaks more than depletion of RNF8, indicating functions other than RNF8-mediated ubiquitination. WRAP53β plays key roles with respect to the nuclear organelles Cajal bodies, including organizing the genome to promote associated transcription and collecting factors involved in maturation of the spliceosome and telomere elongation within these organelles. It is possible that similar functions may aid also in DNA repair. Here we describe the involvement of WRAP53β in Cajal bodies and DNA double-strand break repair in detail and explore whether and how these processes may be linked. We also discuss the possibility that the overexpression of WRAP53β detected in several cancer types may reflect its normal participation in the DNA damage response rather than oncogenic properties.

Objective: The number of adults with congenital heart disease has increased with improvements in surgical and medical management, posing a challenge for regional and rural settings, which might have difficulties accessing specialised professionals with congenital heart disease services. This study aims to ascertain the demographics and management of adults with congenital heart disease seen by a cardiology practice in regional Australia to better understand the needs of regional adults with congenital heart disease., Design: A descriptive study using data from clinical notes collected between April 2013 and April 2016., Setting: A private cardiology practice in Coffs Harbour, New South Wales. The practice has a treating cardiologist, senior sonographer, visiting cardiothoracic surgeon and visiting paediatric cardiologist., Participants: One-hundred-and-one adults with congenital heart disease (age: 16-88 years; 55 women)., Main Outcome Measures: Congenital heart disease defect, lesion severity, referral reason, past surgery, pulmonary hypertension, cardiac surgery during the study, mortality, adherence with follow-up plans and specialist referral., Results: Sixty-six patients had simple congenital heart disease, 24 had congenital heart disease of moderate complexity and 11 had congenital heart disease of great complexity. Most were referred for surveillance, seven were referred due to pregnancy and eight were new diagnoses. Six patients died, nine had cardiac operations and five were treated for pulmonary arterial hypertension. Overall adherence to the treating cardiologist's follow-up plans was 84%. All patients with congenital heart disease of great complexity were referred to congenital heart disease specialists., Conclusion: A substantial number of patients had complex pathology, new diagnoses or required surgery, highlighting the importance of developing integrated services with the close support of outside specialists in managing adults with congenital heart disease in regional settings., (© 2018 National Rural Health Alliance Ltd.)

Background: MYCN is amplified in small cell lung cancers and several pediatric tumors, including alveolar rhabdomyosarcomas and neuroblastomas. MYCN protein is known to play a key oncogenic role in both alveolar rhabdomyosarcomas and neuroblastomas. MYCN opposite strand (MYCNOS) is a gene located on the antisense strand to MYCN that encodes alternatively spliced transcripts, two of which (MYCNOS-01 and MYCNOS-02) are known to be expressed in neuroblastoma and small cell lung cancer with reciprocal regulation between MYCNOS-02 and MYCN reported for neuroblastomas. We sought to determine a functional role for MYCNOS-01 in alveolar rhabdomyosarcoma and neuroblastoma cells and identify any associated regulatory effects between MYCN and MYCNOS-01., Methods: MYCNOS-01, MYCNOS-02 and MYCN expression levels were assessed in alveolar rhabdomyosarcoma and neuroblastoma cell lines and tumor samples from patients using Affymetrix microarray data and quantitative RT-PCR. Following MYCNOS-01 or MYCN siRNA knockdown and MYCNOS-01 overexpression, transcript levels were assayed by quantitative RT-PCR and MYCN protein expression assessed by Western blot and immunofluorescence. Additionally, effects on cell growth, apoptosis and cell cycle profiles were determined by a metabolic assay, caspase activity and flow cytometry, respectively., Results: MYCNOS-01 transcript levels were generally higher in NB and RMS tumor samples and cell lines with MYCN genomic amplification. RNA interference of MYCNOS-01 expression did not alter MYCN transcript levels but decreased MYCN protein levels. Conversely, MYCN reduction increased MYCNOS-01 transcript levels, creating a negative feedback loop on MYCN protein levels. Reduction of MYCNOS-01 or MYCN expression decreased cell growth in MYCN-amplified alveolar rhabdomyosarcoma and neuroblastoma cell lines. This is consistent with MYCNOS-01-mediated regulation of MYCN contributing to the phenotype observed., Conclusions: An alternative transcript of MYCNOS, MYCNOS-01, post-transcriptionally regulates MYCN levels and affects growth in MYCN-amplified rhabdomyosarcoma and neuroblastoma cells.

Background: Caffeinated products are widely available to adolescents, and consumption of caffeine products-energy drinks and coffee in particular-is on the rise in this age group (Branum, Rossen, & Schoendorf, 2014). Yet, little is known about the psychosocial context of caffeine use. Previous studies on adolescent caffeine use have focused on caffeine's acute physiological effects, rather than the psychosocial contexts and beliefs regarding different types of caffeinated beverages (e.g., coffee, energy drinks, soda)., Objectives: The current research examines the contexts and beliefs associated with adolescents' use of caffeinated beverages (e.g., coffee, energy drinks, soda) using a focus group approach., Methods: Eleven focus group interviews (49 total participants) addressed adolescents' motivations for and patterns of caffeine use; they were transcribed and axial coding was used to identify common themes., Results: Coffee and energy drinks were perceived to be the most popular caffeinated beverages. Reasons for consuming caffeine included the effect of caffeine as a stimulant, the pleasant feelings experienced when drinking it, and the fact that caffeine was available. As for contexts, coffee was consumed in more diverse social contexts than other caffeinated beverages. Friends and sports were the most popular contexts for energy drink use., Conclusions: The present findings inform adolescent health promotion efforts and provide researchers and practitioners alike detailed information in adolescents' own words about how and why they use caffeine. Adolescents' beliefs about caffeinated products are not uniform; the reasons adolescents articulate regarding their use of coffee, soda, and energy drinks are different across contexts and beverage type.

Objective: The purpose of this study was to examine whether baseline sleep duration predicts weight loss outcomes in a randomized controlled trial examining a behavioral weight loss (BWL) intervention among overweight and obese (OW/OB) women with urinary incontinence; and whether participation in the BWL intervention is associated with changes in sleep duration., Design: Longitudinal, clinical intervention study of a 6-month BWL program., Subjects: Three hundred sixteen OW/OB women, with urinary incontinence (age: 30-81 years, body mass index (BMI; 25-50 kg m(-2)) enrolled from July 2004-April 2006., Measurements: Measured height and weight, self-report measures of demographics, sleep and physical activity., Results: Neither self-reported total sleep time (TST) nor time in bed (TIB) at baseline significantly predicted weight loss outcomes among OW/OB women in a BWL treatment. BWL treatment was successful regardless of how much subjects reported sleeping at baseline, with an average weight loss of 8.19 kg for OW/OB women receiving BWL treatment, versus a weight loss of 1.44 kg in the control condition. Similarly, changes in weight, BMI and incontinence episodes did not significantly predict changes in sleep duration or TIB across the treatment period., Conclusion: Although epidemiological and cross-sectional studies support a relationship between short sleep and increased BMI, the present study found no significant relationship between TST or TIB and weight loss for OW/OB women participating in a BWL treatment.

The perylenequinones are a novel class of natural products characterized by pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light-activated biological activity, targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this class of compound, as well as several related phenanthroperylenequinones, are reviewed. Natural product modifications that improve biological profiles, and avenues for the total synthesis of analogs, which are not available from the natural product series, are outlined. An overview of structure/function relationships is provided.

Summary: Little is known about the prevalence or impact of insomnia symptoms in obese individuals pursuing bariatric surgery. The present study from the Rhode Island Bariatric Surgery (RIBS) project examined insomnia symptoms among 2300 individuals pursuing bariatric surgery. Patients were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID), Schedule for Affective Disorders (SADS), Rhode Island Bariatric Surgery Interview (RIBSI), and the SF-36 as a measure of quality of life. The presence of insomnia symptoms was determined via ratings for the SCID items assessing initial, middle, and terminal insomnia symptoms, and the SADS insomnia item was used to measure severity of insomnia symptoms. Clinical and demographic variables were obtained from the SCID and self-report measures. Insomnia symptoms were endorsed by 25.8% of participants. Bariatric patients with insomnia symptoms were rated as having a more severe clinical presentation and lower functioning, and were more likely to have a history of psychiatric treatment and/or hospitalization, compared to bariatric patients without insomnia. Linear regression analyses demonstrated that insomnia severity was a significant predictor for scores on each of the 8 SF-36 subscales after accounting for age, gender, race, education level, BMI, depression severity, and sleep apnea. Additionally, a multivariate analysis of covariance (MANCOVA) controlling for depression severity and sleep apnea demonstrated significantly poorer scores on 6 of the 8 SF-36 subscales for bariatric patients with current insomnia symptoms. Results revealed that insomnia symptoms are common among bariatric patients and are associated with reduced quality of life and poorer current functioning. This suggests that insomnia symptoms are an important clinical target in bariatric patients prior to surgery.:, (© 2012 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

Depression is among the most common reasons for seeking psychiatric treatment, and insomnia symptoms are common in the clinical picture of depression. The present study examines the clinical presentation and psychosocial functioning among depressed outpatients with severe symptoms of insomnia in comparison to depressed outpatients without severe insomnia symptoms. The present sample included 2900 treatment-seeking individuals, with 1057 patients having a principal diagnosis of major depressive disorder (MDD). All patients were evaluated using the Structured Clinical Interview for DSM-IV Disorders (SCID), Schedule for Affective Disorders (SADS), and self-report measures of mood and psychosocial functioning. SADS Insomnia ratings were used to determine the presence of severe insomnia symptoms. Clinical, demographic, and psychosocial variables were obtained from the SCID and self-report measures. Among the patients with MDD, 24.7% endorsed severe insomnia symptoms. These individuals were older at time of presentation, were less likely to be married, had a lower education level, had a longer duration of the current depressive episode, were rated as more severe on the CGI, had poorer current functioning via GAF, and had higher HAM-D 21 scores. After controlling for severity, MDD patients with severe insomnia symptoms had poorer social functioning over the past 5 years, though this did not reach the significance level of p < .01, and significantly lower scores on 3 of the 8 SF-36 subscales (p < 0.01). These findings indicate that severe insomnia symptoms are associated with poorer psychosocial functioning and a more severe clinical presentation in patients with MDD. This argues for addressing severe insomnia symptoms among depressed patients, either via behavioral treatment or pharmacologic treatment options., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the Fijian medicinal plant, Dysoxylum richi, possess tumor-specific antiproliferative effects and are thus promising lead candidates., Methods: Because our structure-activity analyses showed that regions flanking the disulfide bond mediated specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives. These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells., Results: Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For example, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p < 0.0001)., Conclusions: Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of compounds for development as anti-cancer agents.

This paper provides a broad review of the extant literature involving the treatment of sleeplessness in older adults with insomnia. First, background information (including information regarding key issues in late-life insomnia and epidemiology of late-life insomnia) pertinent to achieving a general understanding of insomnia in the elderly is presented. Next, theories of insomnia in older adults are examined and discussed in relation to treatment of insomnia in late-life. With a general knowledge base provided, empirical evidence for both pharmacological (briefly) and psychological treatment options for insomnia in late-life are summarized. Recent advances in the psychological treatment of insomnia are provided and future directions are suggested. This review is not meant to be all-inclusive; however, it is meant to provide professionals across multiple disciplines (physicians; psychologists; applied and basic researchers) with a mix of breadth and depth of knowledge related to insomnia in late-life. It is our hope that readers will see the evidence in support of psychological treatments for late-life insomnia, and the utility in continuing to investigate this treatment modality.

Intramolecular 1,8-diketone aldol reactions were studied as a tool for the construction of the seven-membered rings of hypocrellin and shiraiachrome. Conditions were identified to obtain the relative stereochemistries present in the two natural products with excellent diastereoselectivity. In addition, a nine-membered ring congener, which has yet to be observed in nature, formed with high selectivity when a hindered amine was used in conjunction with silazide bases.

Objective: To define patient-determined success criteria for fibromyalgia and back pain treatment across four outcome domains: pain, fatigue, emotional distress, interference with daily activities., Design: Retrospective correlational clinical sample design., Setting: Tertiary care clinics at health science center., Patients: 248 fibromyalgia patients and 52 back pain patients., Interventions: N/A., Outcome Measures: Patient Centered Outcomes Questionnaire, measures of usual pain intensity and pain unpleasantness., Results: Overall, for treatment to be considered successful, fibromyalgia patients required pain levels of 3.30 (54% reduction), fatigue levels of 3.08 (60% reduction), distress levels of 2.49 (60% reduction), and interference levels of 2.67 (63% reduction). Comparatively, back pain patients required pain levels of 2.23 (58% reduction), fatigue levels of 2.29 (57% reduction), distress levels of 1.65 (67% reduction), and interference levels of 1.81 (68% reduction). Overall, both fibromyalgia and back pain patients did not expect to meet their criteria for success., Conclusions: Results highlight the importance of assessing the patient's view of successful outcome. Both fibromyalgia and back pain patients appear to have stringent criteria for success that existing treatments are often unlikely to meet. Comparison across groups indicated fibromyalgia patients have higher usual levels of pain, fatigue, distress, and interference. Interestingly, fibromyalgia patients also require greater changes across domains in order to consider treatment successful, despite rating higher levels of pain, fatigue, distress, and interference as successful. Recognizing patients' success criteria and treatment expectations encourages discussion and development of individualized treatment goals, and wider implementation of individualized treatment for chronic-pain populations is encouraged.

The first total synthesis of (+)-calphostin D and the total synthesis of (+)-phleichrome are outlined. The convergent syntheses utilize an enantiopure biaryl common intermediate, which is formed via an enantioselective catalytic biaryl coupling. The established axial chirality is transferred to the perylenequinone helical stereochemistry with good fidelity. Additionally, efforts focused on the installation of the stereogenic C7,C7'-2-hydroxypropyl groups. Three routes were evaluated to establish the C7,C7'-stereochemistry, in which the successful route involved a double epoxide alkylation with a complex axial chiral biscuprate. This strategy not only allowed the synthesis of the unnatural isomers of calphostin D and phleichrome for assessment in biological systems but also provided valuable information for the syntheses of the more complex cercosporin and hypocrellin A.

An efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A (1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set the centrochiral C7,C7'-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation, a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial chiral intermediate and is then utilized in a dynamic stereochemical transfer to dictate the stereochemistry of the C7,C7'-seven membered ring formed during the aldol cyclization.

Somatic focus refers to the tendency to notice and report physical symptoms, and has been investigated in relation to chronically painful conditions. This study investigated the relationship between somatic focus, as measured by the Pennebaker Inventory of Limbic Languidness (PILL), negative affect and pain. A secondary purpose of the present study was to examine sex differences in these relationships. Participants included 280 chronic pain patients (69.6% females, 88.9% Caucasian), who completed a battery of self-report measures on somatic focus, pain, negative affect, coping, and dysfunction. Results for the overall sample revealed that the PILL shares considerable variance with measures of negative affect, particularly with the physiological components of anxiety and depression. When the results were analyzed separately for male and female patients, it was found that several components of negative affect and cognitive factors play a stronger role in predicting somatic focus among men compared to women. Additional analyses then examined whether somatic focus was predictive of male and female patients' pain reports. Results indicated that somatic focus explained a small, but unique amount of variance in female patients' pain reports, which differed from the relationship observed among male patients.

A palladium-catalyzed aromatic decarboxylation reaction has been developed. With electron-rich aromatic acids, the reaction proceeds efficiently under fairly mild conditions in good yields. The method was useful with complex functionalized substrates containing hindered carboxylic acids.

Transport into the nucleus is critical for regulation of gene transcription and other intranuclear events. Passage of molecules into the nucleus depends in part upon their size and the presence of appropriate targeting sequences. However, little is known about the effects of hormones or their second messengers on transport across the nuclear envelope. We used localized, two-photon activation of a photoactivatable green fluorescent protein to investigate whether hormones, via their second messengers, could alter nuclear permeability. Vasopressin and other hormones that increase cytosolic Ca2+ and activate protein kinase C increased permeability across the nuclear membrane of SKHep1 liver cells in a rapid unidirectional manner. An increase in cytosolic Ca2+ was both necessary and sufficient for this process. Furthermore, localized photorelease of caged Ca2+ near the nuclear envelope resulted in a local increase in nuclear permeability. Neither activation nor inhibition of protein kinase C affected nuclear permeability. These findings provide evidence that hormones linking to certain G protein-coupled receptors increase nuclear permeability via cytosolic Ca2+. Short term regulation of nuclear permeability may provide a novel mechanism by which such hormones permit transcription factors and other regulatory molecules to enter the nucleus, thereby regulating gene transcription in target cells.

This paper discusses current challenges in achieving higher survey participation rates in random-digit-dial telephone surveys and proposes steps to address them through interviewer training to avoid refusals. It describes features of surveys that contribute to respondent reluctance to participate and offers a brief overview of current refusal aversion training methods to reduce nonresponse. It then identifies what challenges that unique features of random-digit-dial telephone surveys on sensitive topics might contribute to nonresponse. Recommendations are then proposed for changes in refusal aversion training, standard survey introductions, and informed consent procedures. Finally, further research is called for to identify which methods best balance the need to improve response rates with respondent safety and privacy in surveys with sensitive questions.

Purpose: Electrosurgery is routinely used in cutaneous surgery for hemostasis. Thermocautery can be used in patients with implantable cardiac devices. This technique relies on heat without electrical current passing through the patient to produce hemostasis. The temperatures and utility of a commercially available, adjustable thermocautery unit are examined., Methodology: Tip temperature of the commercially available thermocautery unit was measured in air and tissue via a type E thermocouple (0.002 in. diameter) around the unit's tip. Time intervals of 20 to 30 seconds were recorded at device settings 1 to 9 in air and 3 to 8 on surgical patients (Institutional Review Board approval obtained)., Results: In vitro analysis demonstrated predictable temperatures at increasing settings in air: 350 to 900 degrees C. Analysis in vivo during surgery demonstrated similar findings. Tissue contact decreased tip temperature by approximately 50% from in vitro values, and use in a bloody field caused a further decrease in the tip temperature., Conclusion: The thermocautery unit examined is an effective and safe unit to achieve hemostasis. In addition, the temperature may be adjusted as opposed to hand-held units that operate at in vitro temperatures exceeding 1,400 degrees F. Hemostasis at approximately 100 to 400 degrees C provided optimal hemostasis.

The primary purpose of this study was to examine the relationship between adolescents' sleep-wake patterns and risk-taking behavior. A second goal was to replicate the results obtained by Wolfson and Carskadon (1998) regarding adolescents' sleep habits. Three hundred eighty-eight adolescents (217 males, 171 females) completed the Sleep Habits Survey and the Youth Risk Behavior Survey. The results indicated that adolescents who reported longer weekend delay and higher levels of sleep problems also reported significantly higher levels of risk-taking behaviors, and students' weekend delay was also related to their academic performance in this sample. As in the sample studied by Wolfson and Carskadon (1998), the adolescents in this study exhibited changes in both weekday and weekend sleep habits across grade/age. However in the present study, only school-night total sleep time and weekend delay were related to adolescents' daytime functioning, with no significant relationships being found between weekend oversleep and daytime functioning. This provides partial support for the findings of Wolfson and Carskadon (1998). Overall, sleep-wake patterns were found to relate to risk-taking behavior during adolescence in this study.

The Boehringer-Ingelheim phosphinoimidazoline (BIPI) ligands were applied to the formation of chiral quaternary centers in the asymmetric Heck reaction. Several different substrates were examined in detail, using more than 70 members of this new ligand class. Hammett relationships were determined through systematic variation of the ligand electronics. All substrates showed essentially the same Hammett behavior, where enantioselectivity increased as the ligands were made more electron-deficient. Ligand optimization has led to catalysts which give the highest enantioselectivities reported to date for these difficult systems., (Copyright 2004 American Chemical Society)

Treatment of cyclic anhydrides with stoichiometric amounts of nickel-neocuproine complex generates alkylcarboxylato-nickelalactones upon extrusion of CO. These metalacycles undergo cross-coupling with arylzinc reagents. The generated CO is sequestered in situ by a nickel-dppb complex. The overall sequence effects a secondary sp3(electrophile)-sp2(nucleophile) cross-coupling and allows for control of stereochemistry during the bond-forming event.

[structure: see text] The new BIPI ligands are phosphinoimidazolines that can be electronically tuned in three different ligand regions to explore electronic effects in asymmetric catalysis. Their application to the asymmetric Heck reaction (AHR) in the creation of a chiral quaternary center is described. Enantioselectivity is shown for the first time to depend linearly on phosphine electron density. Changing the ligand basicity by variation of the R(2) or R(3) substituents reverses facial selectivity.